Disease-specific ACMG/AMP guidelines improve sequence variant interpretation for hearing loss,Genetics in Medicine

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Disease-specific ACMG/AMP guidelines improve sequence variant interpretation for hearing loss
Genetics in Medicine ( IF 8.8 ) Pub Date : 2021-07-06 , DOI: 10.1038/s41436-021-01254-2
Mayher J Patel ₁ , Marina T DiStefano _{1,

2} , Andrea M Oza _{3,

4} , Madeline Y Hughes ₁ , Emma H Wilcox ₁ , Sarah E Hemphill ₃ , Brandon J Cushman ₃ , Andrew R Grant ₁ , Rebecca K Siegert ₁ , Jun Shen _{3,

5} , Alex Chapin ₆ , Nicole J Boczek ₇ , Lisa A Schimmenti ₈ , Kiyomitsu Nara ₉ , Margaret Kenna _{4,

5} , Hela Azaiez ₁₀ , Kevin T Booth _{10,

11} , Karen B Avraham ₁₂ , Hannie Kremer ₁₃ , Andrew J Griffith ₁₄ , Heidi L Rehm _{1,

3} , Sami S Amr _{3,

5} , Ahmad N Abou Tayoun _{15,

16} ,

Affiliation

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Precision Health Program, Geisinger, Danville, PA, USA.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge, MA, USA.
Department of Otolaryngology and Communication Enhancement, Boston Children's Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
ARUP Laboratories, Salt Lake City, UT, USA.
Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN, USA.
Department of Otorhinolaryngology, Clinical Genomics and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa Hospital and Clinics, Iowa City, IA, USA.
Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands.
Department of Otolaryngology Head-Neck Surgery, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA.
Al Genomics Center, Al Jalila Children's Specialty Hospital, Dubai, United Arab Emirates.
Center for Genomic Discovery, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates.

Purpose

The ClinGen Variant Curation Expert Panels (VCEPs) provide disease-specific rules for accurate variant interpretation. Using the hearing loss-specific American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, the Hearing Loss VCEP (HL VCEP) illustrates the utility of expert specifications in variant interpretation.

Methods

A total of 157 variants across nine HL genes, previously submitted to ClinVar, were curated by the HL VCEP. The curation process involved collecting published and unpublished data for each variant by biocurators, followed by bimonthly meetings of an expert curation subgroup that reviewed all evidence and applied the HL-specific ACMG/AMP guidelines to reach a final classification.

Results

Before expert curation, 75% (117/157) of variants had single or multiple variants of uncertain significance (VUS) submissions (17/157) or had conflicting interpretations in ClinVar (100/157). After applying the HL-specific ACMG/AMP guidelines, 24% (4/17) of VUS and 69% (69/100) of discordant variants were resolved into benign (B), likely benign (LB), likely pathogenic (LP), or pathogenic (P). Overall, 70% (109/157) variants had unambiguous classifications (B, LB, LP, P). We quantify the contribution of the HL-specified ACMG/AMP codes to variant classification.

Conclusion

Expert specification and application of the HL-specific ACMG/AMP guidelines effectively resolved discordant interpretations in ClinVar. This study highlights the utility of ClinGen VCEPs in supporting more consistent clinical variant interpretation.

中文翻译：

疾病特异性 ACMG/AMP 指南改进了对听力损失的序列变异解释

目的

ClinGen Variant Curation Expert Panels (VCEPs) 为准确的变异解释提供特定疾病的规则。使用特定于听力损失的美国医学遗传学和基因组学学院/分子病理学协会 (ACMG/AMP) 指南，听力损失 VCEP (HL VCEP) 说明了专家规范在变异解释中的实用性。

方法

HL VCEP 策划了之前提交给 ClinVar 的 9 个 HL 基因的 157 个变体。管理过程包括由生物管理员为每个变体收集已发表和未发表的数据，然后每两个月召开一次专家管理小组会议，审查所有证据并应用 HL 特定的 ACMG/AMP 指南以达到最终分类。

结果

在专家管理之前，75% (117/157) 的变异具有单个或多个意义不确定 (VUS) 提交的变异 (17/157)，或者在 ClinVar (100/157) 中有相互矛盾的解释。在应用 HL 特异性 ACMG/AMP 指南后，24% (4/17) 的 VUS 和 69% (69/100) 的不一致变异被分解为良性 (B)、可能良性 (LB)、可能致病性 (LP) , 或致病性 (P)。总体而言，70% (109/157) 变体具有明确的分类（B、LB、LP、P）。我们量化了 HL 指定的 ACMG/AMP 代码对变体分类的贡献。